Still’s disease

Adult Onset Still’s Disease also known as systemic onset juvenile idiopathic arthritis, adult Still’s disease or Wissler-Fanconi syndrome, is a rare systemic autoummune or autoinflammatory disorder characterized by daily fever, inflammatory polyarthritis, and a transient salmon-pink maculopapular rash ¹. Adult onset Still’s disease can affect any joint, but most commonly involved are knees, wrists, and ankles. Adult-onset Still’s disease begins in adulthood, so it’s compared to rheumatoid arthritis. Inflammation may affect a few joints at first. Over time, more joints may be involved. Some people may have only one bout of the illness followed by lasting remission (no visible symptoms), while others develop chronic arthritis. Adult onset Still’s disease affects men and women equally, usually young adults between the ages of 16 and 35.

The primary clinical features seen in adult-onset Still’s disease are fever, rash, and arthritis or arthralgia. They are seen in about 75 to 95 percent of patients ². Other common symptoms are myalgia, pharyngitis, lymphadenopathy, and splenomegaly. Less commonly observed symptoms are hepatomegaly, pleurisy, pericarditis, and abdominal pain. Fever is usually quotidian (daily recurring fever with temperature returning to normal between fever spikes) most often occurring late during the day and generally precedes other symptoms. The temperature can change by 4ºC within four hours ³. Approximately 20 percent of cases do not have complete defervescence as fever persists between spikes or an additional spike occur in the morning(double quotidian fever). It may also present as fever of unknown origin (FUO), and a temperature of more than 39.5ºC suggests monophasic pattern more strongly ⁴. A rash is classically evanescent, salmon-colored, macular or maculopapular which is usually nonpruritic and occurs with the fever. It is mainly seen on the trunk and extremities but can also be seen on palms, soles, and the face. The rash can sometimes be induced by heat(hot shower or towel) or by rubbing the skin(Koebner phenomenon). Arthritis can initially be mild, transient, and oligoarticular and may evolve to severe, destructive and symmetric polyarticular forms ⁵. Commonly involved joints are the knees, wrists, and ankles, although elbows, proximal interphalangeal joints, shoulders, metacarpophalangeal, metatarsophalangeal, hips, distal interphalangeal and temporomandibular joints can also be involved. Fusion of the wrist joint is characteristic of adult onset Still’s disease but is seen in only a few patients. Myalgia often gets worse with fever spikes. It may sometimes be severe and debilitating. Muscle weakness is not present, but case reports have described a slight elevation of serum creatine kinase and aldolase. Usually, electromyographic studies and muscle biopsies are either normal or may show a nonspecific inflammatory myopathy.

Patients can present with a sore throat at the time of initial evaluation and it frequently recurs during a disease flare. Examination in those cases typically reveals severe, nonsuppurative pharyngitis with negative bacterial cultures. A review of 341 cases of adult onset Still’s disease has described a sore throat in 69% of the patients ⁶. Symmetrical slightly tender lymphadenopathy is reported in one-third to two-thirds of patients, and splenomegaly in one-third to one-half of patients. Liver abnormalities include hepatomegaly ranging from 12 to 45 percent ² and more commonly modest elevations of serum hepatic transaminases and alkaline phosphatase. About 30 to 40 percent of patients with adult onset Still’s disease have pericarditis, pleural effusions, and transient pulmonary infiltrates ². Macrophage activation syndrome occurs in a small minority of patients but it may be underdiagnosed as suggested by retrospective studies in which macrophage activation syndrome occurred in six out of 50 patients and 21 out of 109 patients ⁷. Abdominal pain occurs in 1 to 48 percent of the patients. Nausea, anorexia, and weight loss can also be seen.

Adult-onset Still’s disease is a very uncommon disease. Its annual incidence has been estimated to be 0.1 to 0.4 cases per 100,000 people in Europe. Females are affected slightly more than males. It has bimodal age distribution, the first peak between the ages of fifteen to twenty-five and the second between thirty-six to forty-six. However, about three-quarters of the patients report the onset of disease between sixteen and thirty-five years of age.

Diagnosis is based on review of symptoms, medical history, physical examination and possibly laboratory tests. There is no single test that can diagnose adult Still’s disease. Instead, blood tests are used to rule out other diseases with similar symptoms. Other tests, such as X-rays, may be done to check for joint inflammation or damage. Even though there is no specific diagnostic test, a serum ferritin level more than 1000ng/ml is common in adult onset Still’s disease.

Doctors use several drugs to treat adult Still’s disease. Over-the-counter or prescription nonsteroidal anti-inflammatory drugs (NSAIDs) help to reduce mild pain and inflammation. Corticosteroids, such as prednisone, are needed if the disease is severe or doesn’t respond to prescription NSAIDs. Disease-modifying drugs (DMARDs), such as methotrexate, and biologics, are needed in more severe cases or if the arthritis becomes chronic. It may be necessary to take more than one medication at a time to control symptoms.

With adult Still’s disease, the medications may need to be taken even after symptoms go away. This is called maintenance therapy. It’s important to keep inflammation under control to prevent damage to joints and organs.

Figure 1. Adult onset Still’s disease rash

Still’s disease cause

The cause of adult onset Still’s disease is unknown. Research suggests that it may be triggered by an infection. The hypothesis remains that adult onset Still’s disease is a reactive syndrome in which various infectious agents may act as triggers in a genetically predisposed host. Both genetic factors and a variety of viruses, bacteria like Yersinia enterocolitica and Mycoplasma pneumonia and other infectious factors have been suggested as important ⁸. There is uncertainty regarding the presence of same etiopathogenic factors among all the adult onset Still’s disease patients. A French study of 62 patients showed the association of adult onset Still’s disease with HLA antigen subtypes ⁹.

Still’s disease pathophysiology

There are two immune dysregulations described in the pathogenesis of adult onset Still’s disease. Innate immunity with neutrophil and macrophage activation under the effect of proinflammatory cytokine IL-18 is one pathway. A study has shown the upregulation of CD64 in active adult onset Still’s disease which is a marker of neutrophil activation ¹⁰. Secondly, CD4+ T helper (Th) cells may also play a role in the pathogenesis of adult onset Still’s disease with the predominance of Th1 subset over Th2 as seen in a study which showed significantly higher expression of interferon-gamma mRNA expression than interleukin-4 in tissue biopsies ¹¹. Moreover, the role of Th-17 responses is emerging in the pathogenesis of adult onset Still’s disease, and levels of Th-17 related cytokines, interleukins-1,6,17,18,21 and 23 are elevated.

Still’s disease symptoms

The symptoms, progression and severity of adult onset Still’s disease are highly variable from one person to another. Adult onset Still’s disease symptoms usually begin with a high fever that spikes once or twice a day and a salmon-pink rash on the trunk, arms or legs. Other symptoms include sore throat and swollen lymph nodes in the neck.

Almost all people with Still’s disease will have fever, joint pain, sore throat, and a rash.

• Joint pain, warmth, and swelling are common. Most often, several joints are involved at the same time. Often, people with the condition have morning stiffness of joints that lasts for several hours.
• The fever comes on quickly once per day, most commonly in the afternoon or evening.
• The skin rash is often salmon-pink colored and comes and goes with the fever.

Additional symptoms include:

• Abdominal pain and swelling
• Pain when taking a deep breath (pleurisy)
• Sore throat
• Swollen lymph nodes (glands)
• Weight loss

The spleen or liver may become swollen. Lung and heart inflammation may also occur.

A few weeks after these initial symptoms, joints and muscles begin aching. These aches last at least two weeks. The most commonly affected joints are the knee and wrist. The ankles, shoulders, elbows and finger joints may also be involved.

Some individuals may only develop one random episode that responds to treatment and resolves within one year. In some cases, a new episode does not occur or does not occur until many years later. Other individuals may develop chronic disease, in which episodes come and go, often years apart and with no symptoms in-between episodes. Still other individuals may experience frequent episodes that occur every several weeks or months. Individuals with chronic adult onset Still’s disease may have a form predominantly characterized by fever or a form predominantly characterized by joint disease (chronic arthritis). Chronic adult onset Still’s disease can potentially cause long-term, severe and disabling complications.

Most individuals with adult onset Still’s disease develop some combination of the symptoms normally associated with systemic inflammatory disease. Such symptoms include a spiking fever greater than 102.2 degrees Fahrenheit (39 degrees Celsius), joint pain (arthralgia) and inflammation (arthritis), muscle pain (myalgia), and a skin rash.

In some cases, fevers are a daily occurrence and usually peak or spike in the late afternoon or early evening. In rare cases, some individuals develop two spiking fevers in one day. The rash is pink or salmon colored, and usually develops during a fever episode. The chest and thighs are most often affected by the rash. The arms, legs and face are affected less often. The rash may or may not be itchy and tends to disappear quickly (evanescent).

Affected joints may become swollen, stiff and inflamed and may persist for a couple of weeks. The knees, wrists and ankles are most commonly affected. Muscle and joint pain can be intense and is often worse during a fever episode. If adult onset Still’s disease goes untreated, chronic inflammation of the joints can potentially result in deterioration and destruction of the affected joints.

Additional findings may occur in some cases including a sore throat, enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly), and enlargement of the lymph nodes (lymphadenopathy).

In some cases, the thin, sac-like membrane that surrounds the heart (pericardium) or the heart muscle (myocardium) may become inflamed (pericarditis or myocarditis). The membrane lining the chest cavity may also become inflamed and may cause fluid to accumulate in the lungs (pleural effusion). Heart and lung involvement can cause difficulty breathing and chest pain, but in most cases it is usually not severe enough to be readily apparent and is often only detected during a physical examination by a physician.

Still’s disease complications

Adult onset Still’s disease complications include macrophage activation syndrome, amyloidosis, disseminated intravascular coagulopathy, pulmonary arterial hypertension, thrombotic thrombocytopenic purpura, and diffuse alveolar hemorrhage.

Still’s disease diagnosis

The diagnosis of adult onset Still’s disease is difficult because there are no specific tests or distinguishing laboratory (histopathologic) findings that clearly differentiate the disorder from similar disorders. Instead, blood tests are used to rule out other diseases with similar symptoms. Other tests, such as X-rays, may be done to check for joint inflammation or damage.

Adult onset Still’s disease diagnosis is usually made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and the exclusion of other possible disorders (diagnosis of exclusion). A variety of tests may be performed to aid in a diagnosis including blood tests and x-ray studies that reveal changes in the bones or joints or enlargement of the spleen or liver. An echocardiogram, which uses sound waves to create a picture of the heart, may reveal inflammation of the pericardium or myocardium.

Blood tests may reveal characteristic changes to blood cell levels normally associated with adult onset Still’s disease. Affected individuals often have elevated levels of white blood cells and/or platelets or low levels of red blood cells. A common blood test for individuals suspected of having an inflammatory disorder is an erythrocyte sedimentation rate. Sedimentation rate measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period. Many individuals with adult’s onset Still’s disease have an elevated sedimentation rate, which is an indication of inflammation. Another blood test commonly used is serum ferritin that is frequently disproportionally elevated in adult onset Still’s disease.

At least seven different variety of classification criteria for adult onset Still’s disease are there for use in research. The Japanese standards termed the Yamaguchi criteria ¹² has the highest sensitivity amongst them and is the most commonly used.

Total of five or more criteria including 2 or more significant criteria have a sensitivity of 96% and specificity of 92% to classify a patient as having adult onset Still’s disease.

Major criteria are as follows:

• Fever of at least 39°C for at least one week
• Arthralgia or arthritis for at least two weeks.
• Nonpruritic salmon-colored rash on trunk/extremities.
• Granulocytic leukocytosis (10,000/microL or greater).

Minor criteria are as follows:

• A sore throat.
• Lymphadenopathy.
• Hepatomegaly or splenomegaly.
• Abnormal liver function tests. Negative tests for rheumatoid factor (RF) and antinuclear antibody (ANA).

The lab findings discussed below are characteristic of adult onset Still’s disease, but not pathognomonic and hence their presence along with clinical manifestations will help the clinician in establishing the diagnosis after ruling out alternate causes.

Inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in almost all the patients ⁹. Leukocytosis, generally more than 15,000 cells/microL with a predominance of neutrophils greater than 80%, normocytic normochromic anemia and thrombocytosis are the hematological findings. These hematological abnormalities can be severe enough to mimic primary hematologic disease. Bone marrow biopsy has been reported to show hyperplasia of granulocytic precursors and hypercellularity and hemophagocytosis in some cases. Hepatic transaminases can be elevated in 75 percent of patients and aldolase can also elevate in some due to liver inflammation.

Ferritin levels are generally higher than five times the upper limits of normal in patients with adult onset Still’s disease. Elevated ferritin suggests the presence of the disease with an 80% sensitivity and 46% specificity. If combined with a decrease in the proportion of glycosylated ferritin <20%, the specificity will rise to 93%.

Less than 10% of the patients have Antinuclear antibodies (ANA) and rheumatoid factor (RF) but generally only in low titer.

The synovial fluid is usually inflammatory with a mean leukocyte range of 100 to 48,000 cells/microL ⁹.

Radiographs early in the disease typically are either normal or show slight joint space narrowing or periarticular osteopenia. Narrowing of the wrist carpometacarpal and intercarpal joint spaces which may progress to bone ankylosis is a classic radiographic finding of adult-onset Still’s disease (adult onset Still’s disease) ¹³.

Still’s disease treatment

The goals of therapy include controlling symptoms and physical signs of inflammation as well as laboratory markers of inflammation. It also includes preventing end-organ damage and keeping the long term effects of therapy to the minimum.

The efficacy of treatment interventions for adult onset Still’s disease is derived from observational studies and clinical experience ¹⁴.

The initial therapeutic decisions are based upon the degree of disease activity and the subsequent ones based on the clinical response.

The mild disease presents with fevers, rash, arthralgias or mild arthritis. The patients with mild disease may respond to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are most often used first, but most of them require at least a low dose of glucocorticoid for better control. The dose of NSAIDs is in anti-inflammatory range.

The moderate disease presents with debilitating joint symptoms, high-grade fever or internal organ involvement which is not life-threatening. The patients with moderate disease severity are initially treated with glucocorticoids initiated with prednisone 0.5 to 1 mg/kg per day, depending upon disease severity. Biologic, as well as non-biologic disease-modifying antirheumatic drugs, might be needed if the steroids cannot be successfully tapered. Anakinra is favored as the initial agent in patients without joint erosions, and methotrexate is preferred in patients with prevalent joint disease.

Those with severe disease have life-threatening organ involvement like cardiac tamponade, disseminated intravascular involvement or severe hepatic involvement. Those with severe disease require initial therapy with pulse IV methylprednisolone 1000 mg daily for three days, and this approach has been proven effective in many case reports and series ¹⁵. Early use of biologic therapy is also recommended in severe disease. Among biologics, IL-1 inhibitor Anakinra and IL-6 inhibitor Tocilizumab are more effective than TNF inhibitors. Limited evidence suggests that Canakinumab, Rilonacept, Rituximab, and Abatacept may be effective in treating patients who are refractory to therapies as mentioned above.

Self care

Caring for the body and mind are key components of an adult Still’s disease management plan. Make positive and healthy lifestyle choices and acknowledge the physical and emotional effects of arthritis. Proper nutrition, activity, rest and following doctors’ orders are important for managing the condition and possible medication side-effects.

Still’s disease prognosis

The course of adult onset Still’s disease generally follows one of the three patterns – self-limited illness, intermittent flares or chronic Still’s disease. There are several predictors for the chronicity of the disease and the unfavorable outcomes. It includes the presence of an erosive polyarthritis at the time of presentation and involvement of shoulders or hips ⁹. The need for systemic glucocorticoids for more than two years before routine use of biologics is also considered a poor prognostic marker.

References

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